Diabetes is a syndrome mainly characterized by chronic continuance of a high concentration of glucose in blood (blood glucose level) and is a disease caused by relative or absolute deficiency of insulin which is a blood glucose-lowering hormone.
The number of diabetic patients throughout the world is currently estimated to be 194,000,000 (2003, adults), accounting for 5.1% of the adult population (3,800,000,000), which corresponds to a diabetic morbidity of one in twenty people. Further, this number is predicted to rise to 333,000,000 by 2025 (Diabetes Atlas, 2003, 2nd edition, p. 15-71).
Further, there is a serious increase in the number of people with impaired glucose tolerance which can be said to be a pre-diabetes state. Impaired glucose tolerance raises a pathogenic risk of hypertension or hyperlipidemia as well as a pathogenic risk of diabetes. The number of people with impaired glucose tolerance in the adult population is already estimated to be 314,000,000, and is said to be increased to 472,000,000 by 2025. Therefore, it is said to the extent that diabetes and impaired glucose tolerance are called the most significant medical problem of the 21st century, there is a great social demand associated with the treatment of this diseases.
In healthy people, saccharides from dietary intake are absorbed by the digestive tract and then transported into blood, resulting in elevation of the blood glucose level. Correspondingly, insulin is secreted from the pancreas, whereby release of glucose from the liver is lowered while increasing glucose uptake into muscle or adipose tissues. Then, the blood glucose level is decreased. As a result, homeostasis of blood glucose is maintained. However, in a diabetic condition, it is caught in chronic dysfunction of the blood glucose control known as postprandial hyperglycemia or fasting hyperglycemia due to incomplete secretion of insulin, or insulin resistance (insufficiency of insulin action).
Chronic duration of a hyperglycemic state leads to an enhancement in the production of reactive oxygen in vivo, which consequently increases oxidative stress to vascular endothelial cells. Indeed, it has been reported that the level of an oxidative stress marker in blood is elevated in diabetic patients. It is considered that oxidative stress stemming from such a hyperglycemic condition is closely correlated with not only the progression of diabetes (hyperglycemic symptom), but also the pathogenesis of microvascular diabetic complications such as diabetic retinopathy, neuropathy, and nephropathy (Non-Patent Citation 1).
Excessive reactive oxygen also acts on lipids in vivo to cause the formation of lipid peroxides such as oxidized LDL, which, in turn, brings about inflammatory reactions including the accumulation of monocytes and macrophages in the vascular endothelium, and macrovascular complications (arteriosclerosis) accompanying the risk of cardiovascular events.
In vivo oxidative stress arises from the excessive production of reactive oxygen species (ROS) such as superoxide anions. NAD(P)H oxidase in neutrophils or phagocytes has been conventionally known as a principle production source of ROS for a long time. Recently, the production of ROS by NAD(P)H oxidase has also been confirmed in several cellular species such as vascular endothelial cells or smooth muscle cells, and the possibility has been pointed to that ROS is implicated in functions of cells and the pathogenesis of diseases in a variety of tissues (Non-Patent Citation 2).
In insulin target cells such as L6 myocytes or 3T3-L1 adipocytes, it has been reported that long-term exposure of ROS to such cells inhibits glucose uptake by insulin stimulation (Non-Patent Citations 3 and 4), and it is believed that oxidative stress induces insulin resistance. Besides, it is believed that ROS produced by chronic hyperglycemia results in dysfunction or apoptosis of pancreatic β cells, consequently lowering insulin secretion (Non-Patent Citation 5).
In diabetic model mice, it has been reported that an expression level of NAD(P)H oxidase is increased in adipose tissues, thus enhancing the production of ROS, and apocynin, an NAD(P)H oxidase inhibitor, inhibits ROS production lower the blood glucose level in diabetes model mice (Non-Patent Citation 6). In addition, it has been reported that diphenyleneiodonium (DPI), another NAD(P)H oxidase inhibitor, promotes glucose uptake into L6 myocytes and improves insulin sensitivity in diabetes model mice (Patent Citation 1).
From these findings, a compound inhibiting the NAD(P)H oxidase activity, based on an inhibitory action of ROS production, is expected to be a drug for improving hyperglycemic symptoms in diabetes through the promotion of glucose uptake in peripheral tissues. Further, with regard to the pancreas or other organs vulnerable to disorders through diabetic hyperglycemia, such a compound also provides a feasibility of a drug having an active protective action via the relief of oxidative stress.
Apocynin, which is an NAD(P)H oxidase inhibitor, has been reported to improve the elevation of triglyceride levels in blood and hepatic tissues in diabetes model mice (Non-Patent Citation 6), and a compound inhibiting an NAD(P)H oxidase activity is also considered to be useful for preventing and treating hyperlipidemia or fatty liver.
Besides, elevation of blood pressure due to a rise of ROS production in vascular walls through the action of NAD(P)H oxidase has been reported in spontaneous hypertension model rats, or hypertension model rats with continuous administration of angiotensin II (Non-Patent Citation 7), and an NAD(P)H oxidase inhibitor is expected to remedy hypertension.
Further, it is considered that a rise of ROS production through the action of NAD(P)H oxidase is involved in the pathogenesis and progression of diabetic complications (such as retinopathy, nephropathy, and neuropathy), peripheral circulatory disturbance, and arteriosclerosis, by the development of vascular endothelial cell disorders and chronic inflammatory reactions (Non-Patent Citation 8), and there is a possibility that the NAD(P)H oxidase inhibitor inhibits these diseases.
Additionally, as diseases associated with an enhancement of ROS production, there are known metabolic syndromes (Non-Patent Citation 5), Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steato-Hepatitis (NASH) (Non-Patent Citation 9), cancer (Non-Patent Citation 10), Alzheimer's type dementia (Non-Patent Citation 11), age-related macular degeneration (Non-Patent Citation 12), neurodegenerative diseases, cerebral stroke, ischemic diseases, arthritis, inflammatory diseases, etc. (Non-Patent Citation 13). The NAD(P)H oxidase inhibitor is expected to ameliorate these diseases.
As the NAD(P)H oxidase inhibitor, bicyclic pyridazine compounds have been reported to be effective for treating diabetes, hypertension, and the like (Patent Citation 2).
Meanwhile, there have been reported Patent Citations 3 through 8, Non-Patent Citation 14, and the like relating to quinolone derivative compounds.
It has been reported in Patent Citation 3 that a compound of the formula (A) exhibits a leucotriene D4 antagonistic action and is effective for allergic diseases. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity.

(In the formula, A represents —CH2CH═CH—, —CH(OH)CH═CH—, —CH(OH)C≡C—, —CH═CHCH2—, or —CH2C≡C—. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 4 that a compound of the formula (B) exhibits an anti-helicobacter pylori action. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.

(In the formula, A represents —CH(OH)CH═CH—, —CH(OH)C≡C—, —CH═CHCH2—, —(CH2)n—, —CH═CHCH2—, —CH═CHCH═CH—, —COCH2—, or —CH2CH═CH—, and B represents a hydrogen atom, —(CH2)p—CH3, (CH2)q—CO2H, or —CH2CH═C(CH3)CH2CH2CH═C(CH3)—CH3. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 5 that a wide range of compounds represented by the formula (C) exhibit an anti-helicobacter pylori action. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.

(In the formula, R2 means

See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 6 that a compound of the formula (D) exhibits an anti-helicobacter pylori action. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.

(In the formula, R2 represents C1-10 alkyl, C2-10 alkenyl, (C1-10 alkyl)phenyl, (C2-10 alkenyl)phenyl, C2-10 alkynyl, (C2-10 alkynyl)phenyl, phenyl, naphthyl, thiophenyl, or pyridyl (provided that a cyclic group may be substituted). See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 7 that a wide range of compounds represented by the formula (E) exhibit an inosine monophosphate dehydrogenase (IMPDH) inhibitory activity. However, there is no specific disclosure of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.

(In the formula, R1 represents alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 8 that 2-(2-heptenyl)-3-methyl-4(1H)-quinolone, 2-(2-cis-heptenyl)-3-methyl-4(1H)-quinolone, and 2-(2-trans-heptenyl)-3-methyl-4(1H)-quinolone exhibit an anti-helicobacter pylori action. However, there is no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
It has been reported in Patent Citation 9 that a wide range of compounds represented by the formula (F) exhibits a PPAR receptor inhibitory activity. However, there is no specific disclosure of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity.

(In the formula, Ar I and Ar II represent aryl, heteroaryl, or the like. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 14 that 3-methyl-2-(5-phenoxypentyl)quinolin-4(1H)-one and 3-ethyl-2-(5-phenoxypentyl)quinolin-4(1H)-one have an NADH-ubiquinone reductase inhibitory action. However, there is no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
It has been reported in Patent Citation 15 that 3-methyl-2-[2-(4-phenoxyphenyl)ethyl]quinolin-4(1H)-one has an NADH-ubiquinone reductase inhibitory action. However, there is no disclosure of NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
A synthesis method of 3-chloro-2-(piperidin-1-ylmethyl)quinolin-4(1H)-one has been reported in Patent Citation 16. However, there is no disclosure of NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
[Patent Citation 1] Pamphlet of International Publication No. WO2003/087399
[Patent Citation 2] Pamphlet of International Publication No. WO2004/089412
[Patent Citation 3] European Patent Application Laid-open Publication No. 374765
[Patent Citation 4] JP-A-2001-97866
[Patent Citation 5] Pamphlet of International Publication No. WO97/12864
[Patent Citation 6] European Patent Application Laid-open Publication No. 811613
[Patent Citation 7] Pamphlet of International Publication No. WO01/81340
[Patent Citation 8] JP-A-10-279561
[Patent Citation 9] Pamphlet of International Publication No. WO00/064888
[Non-Patent Citation 1] Brownlee, Nature, 2001, Vol. 414, p. 813-820
[Non-Patent Citation 2] Griendling et al., Circulation Research, 2000, Vol. 86, p. 494-501
[Non-Patent Citation 3] Blair et al., The Journal of Biological Chemistry, 1999, Vol. 274, p. 36293-36299
[Non-Patent Citation 4] Rudich et al., Diabetes, 1998, Vol. 47, p. 1562-1569
[Non-Patent Citation 5] Ihara et al., Diabetes, 1999, Vol. 48, p. 927-932
[Non-Patent Citation 6] Furukawa et al., The Journal of Clinical Investigation, 2004, Vol. 114, p. 1752-1761
[Non-Patent Citation 7] Fukui et al., Circulation Research, 1997, Vol. 80, p. 45-51
[Non-Patent Citation 8] Inoguchi et al., Current Drug Targets, 2005, Vol. 6, p. 495-501
[Non-Patent Citation 9] Browning et al., The Journal of Clinical Investigation, 2004, Vol. 114, p. 147-152
[Non-Patent Citation 10] Arbiser et al., Proceedings of the National Academy of Science, 2002, Vol. 99, p. 715-720
[Non-Patent Citation 11] Zhu et al., Brain Research, 2004, Vol. 1000, p. 32-39
[Non-Patent Citation 12] Imamura et al., Proceedings of the National Academy of Science, 2006, Vol. 103, p. 11282-11287
[Non-Patent Citation 13] Droge et al., Physiological Reviews, 2002, Vol. 82, p. 47-95
[Non-Patent Citation 14] Chung et al., Journal of Bioscience, 1989, Vol. 44, p. 609-616
[Non-Patent Citation 15] Chung et al., Journal of Korean Agricultural Chemical Society, 1990, Vol. 33, p. 264-267
[Non-Patent Citation 16] Braun et al., Berichte der Deutschen Chemischen Gesellshaft, 1930, Vol. 63(B), p. 3291-3203